Dissertation

Development and optimization of various novel nanoparticle formulation methods for poorly soluble drugs into soluble and insoluble carriers and characterization of their supersaturated drug release patterns

Patel, Mehulkumar A

2018

Overview

Drugs with poor aqueous solubility and slow dissolution present a big hurdle for formulation scientists. Numerous techniques are available to overcome this challenge, and supersaturation drug delivery system through particle size reduction and solubilization of drug in oil are particularly promising approaches. Reduction in drug particle size to the nanometer scale can increase the total surface area of the dissolving drug, which can improve dissolution and bioavailability. Also, the solubilized drug in oil plus the large surface area of nanoscale oil globules enhances dissolution and bioavailability. In this project, the two approaches are proposed to produce nanoformulations. The first approach is to produce drug particles in the pores of excipients such as Syloid® 244FP (a porous insoluble excipient). This was done for the model drug ibuprofen (IBU) by imbibing concentrated solutions of IBU in organic solvents (ethanol and acetone) into the Syloid 244FP pores, then removing the solvent by evaporation. This technique is unique because it loads the drug into the pores rather than the outer surface of the carrier particle. It produces the size reduction of drug particles without applying any force or mechanical pressure and heat, which makes it a suitable technique for thermolabile materials. Importantly, it maintains the stability of supersaturated dosage forms by inhibiting confined drug particles motion in tiny pores. In addition, high surface area and surface energy of pore walls inhibit or delay the nucleation and growth. To develop a successful supersaturated formulation, investigation of physicochemical factors and process parameters are unavoidable. Drug concentration, solvents, carrier, soaking time, drug loading mechanisms, wash solvent, etc. were optimized as they are very crucial to control drug release rate from the pores. The supersaturated drug release patterns were also analyzed to understand the formulation process better. The second unique approach includes the development of IBU microemulsion (selfmicroemulsifying drug delivery system, SMEDDS), which are then loaded onto SuperTab® 30GR (a water-soluble excipient) by mixing the microemulsion and SuperTab 30GR, then removing the water by evaporating at 40 °C. This nanoformulation has combined advantages of SMEDDS and solid dosage form. When introduced into a dissolution medium, the water mixes with the formulation to re-produce the microemulsion with very small (nanometer-scale) globules, and the drug is subsequently released. The very small globule size results in a very large surface area, which imparts higher release rates for the drug into the dissolution medium. However, there are numerous problems associated with SMEDDS formulations that can be solved by transforming lipid form into solid form using this technique. The preconcentrate:SuperTab 30GR and oil:surfactant ratios were optimized as they are significant parameters for this type of formulation development. Also, drug release patterns were analyzed to understand drug release mechanisms. Experimental results with IBU demonstrated that both nanoformulation methods significantly enhanced IBU solubility and dissolution rate. It was found that the drug could be loaded into the Syloid pores by two mechanisms, one based on solution imbibing and another based on drug diffusion into the pores from a bulk solution, thus providing options in producing the formulations. The drug melting point depression in thermal analysis confirmed successful deposition of the drug into the pores and size reduction of deposited drugs into the pores. The IBU-Syloid 244FP nanoformulations showed 2.5 times higher drug release compared to pure IBU solubility in PBS pH 2, and some formulations produced \"spring and parachute\" release patterns. Surprisingly, in some cases, the drug loading on Syloid did not correlate well with drug release rates, which suggested only drug loading study is not sufficient to measure to develop nanoformulations, but the drug release study is also a good navigator for nanoformulation development. The percentage drug loss from the samples subjected to aging was minor, indicating the systems were stable. The thermal analysis of IBU-SuperTab® 30GR nanoformulations displayed an absence of drug melting peak in DSC thermograms, which confirmed drug dissolved in lipidic globules in nanoformulations. The changes in globule size were minor before loading drug microemulsions on SuperTab 30GR and after dissolving final formulations into dissolution media. That confirmed that the microemulsions reformed with a very small globule size, when formulations come in contact with dissolution media. The small globule size of re-formed microemulsions results in a huge surface area associated with this type of system. The combined effect of drug solubilized in oil globules plus the huge surface area of oil globules resulted around 27-fold increase in drug solubility and dissolution rate from IBU-SuperTab 30GR nanoformulations compared to pure IBU solubility in PBS pH 2. In microemulsion, the drug is already dissolved in the globule phase during the formulation process, thus avoiding the need for the dissolution step in drug release. This may be the primary reason for higher drug release achieved from the SuperTab formulations compare to Syloid formulations. The percentage drug loads and in-vitro release profiles of stored samples remained the same compared with initial samples, indicating the drug in nanoformulations was stable. To prove these novel nanoformulation methods, analogous formulation work was done using another model drug, griseofulvin (GRIS) with another insoluble porous carrier, Neusilin® US2 and with a soluble carrier, SuperTab 30GR. The GRIS nanoformulations displayed similar characteristics to those seen with IBU nanoformulations. This indicated that the nanoformulation methods developed in this research are not specific to one drug or carrier but are also applicable to many poorly soluble drugs and pharmaceutical carriers. Also, the effects of different particle size of porous carriers, Syloid ® 244FP (particle size 3.5 µm) and Syloid® XDP 3150 (particle size 150 µm) on nanoformulations performance were investigated by formulating IBU-Syloid 244FP and IBU-Syloid XDP 3150 nanoformulations, and comparing drug loading, in-vitro drug release, and thermal analysis. The drug load achieved on Syloid 244FP was more than double than Syloid XDP 3150. The in-vitro drug release was higher from Syloid 244FP than Syloid XDP 3150 due to the higher surface area offered by the small particle size of Syloid 244FP than Syloid XDP 3150. However, both Syloid formulations demonstrated around twofold higher drug release than crystalline IBU solubility in PBS pH 2. The drug melting peak was depressed in both Syloid nanoformulations compared to pure drug. Also, the drug melting peak was more depressed in Syloid 244FP than Syloid XDP 3150 formulations, which indicated drug particle size in Syloid 244FP was smaller than in Syloid XDP 3150 that might be the reason for the better performance of Syloid 244FP than Syloid XDP 3150. In essence, the nanoformulations produced by these two methods are capable enough to produce and maintain supersaturation for enough time frame in dissolution media, which can enhance solubility and dissolution rates of poorly soluble drugs and can enhance bioavailability.

• Publisher: ProQuest Dissertations & Theses
• Subject: Materials science / Nanotechnology / Pharmaceutical sciences
• ISBN: 0438075773, 9780438075771